Despite early recognition of the importance of internal cues (craving sensations and emotional states) for relapse in substance use disorders, relatively little attention has been devoted to exposure-based treatments targeting these cues. As part of a NIDA Phase I trial, we developed and pilot tested a treatment that emphasizes internal (largely emotional) cue exposure for substance use disorders. Our model for this treatment was based on the role of exposure to feared sensations of anxiety in the treatment of panic disorder and benzodiazepine discontinuation, as well as the importance of attending to these fears in treatments of stress-related conditions such as posttraumatic stress disorder (PTSD). This model of treatment gained further support from recent research on the link between drug-use motives and intolerance to internal cues as assessed by biological provocation procedures and measures such as the Anxiety Sensitivity Index. In accordance with this research, our treatment focuses on the value of internal cue exposure strategies for individuals who use substances as a way to cope with negative affect and stress. In particular, rather than focusing on "attenuating the affective signal" arising from stress, we focus on: (1) enhancing a patient's tolerance to the myriad forms of distress--sadness, boredom, anxiety, withdrawal sensations, etc.--that are linked to the stressful lives of drug-dependent individuals, and (2) breaking the link between these emotional cues and drug-related attempts to avoid emotional distress. Because of its focus on changing responses to internal cues, we titled our treatment, Cognitive-Behavioral Therapy for Interoceptive Cues (CBT-IC). In response to RFA DA-04-001 we are proposing a 5-year study designed to test further the efficacy of CBT-IC for intervening with chronically stressed and treatment-resistant opiate-dependent outpatients. Features of this study of particular relevance to the RFA include: (1) a focus on opiate-dependent patients undergoing chronic stress; (2) a model for the way in which chronic stress translates into chronic drug use; (2) a focus on the way in which stress-related symptoms serve as trigger for drug use; (3) a focus on both mediators and moderators of treatment that will inform treatment-matching efforts, including a focus on gender differences and emotional avoidance/distress intolerance and (4) the examination of treatment outcome in a Stage II treatment trial.